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Science. 2015 Oct 16;350(6258):325-8. doi: 10.1126/science.aac6948.

Suboptimization of developmental enhancers.

Author information

1
Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. msl2@princeton.edu ekfarley@princeton.edu.
2
Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
3
Department of Medicine, University of California, San Diego, CA 92093-0688, USA.
4
Department of Chemistry, University of California, Berkeley, CA 94720-3200, USA.
5
Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA.

Abstract

Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities ("suboptimization"). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs. Perfect matches mediate robust but ectopic patterns of gene expression. The native sites are not arranged at optimal intervals, and subtle changes in their spacing alter enhancer activity. Multiple tiers of enhancer suboptimization produce specific, but weak, patterns of expression, and we suggest that clusters of weak enhancers, including certain "superenhancers," circumvent this trade-off in specificity and activity.

PMID:
26472909
PMCID:
PMC4970741
DOI:
10.1126/science.aac6948
[Indexed for MEDLINE]
Free PMC Article

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